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Induction Isatuximab-RVd Combo Boosts MRD Negativity in Multiple Myeloma

— Half of newly diagnosed, transplant-eligible patients reached minimal residual disease negativity

MedpageToday

ATLANTA -- Patients with newly diagnosed, transplant-eligible multiple myeloma (MM) who received isatuximab (Sarclisa) combined with standard treatment as induction therapy were more likely to achieve minimal residual disease (MRD) negativity than patients treated with standard therapy alone, a researcher reported.

In the GMMG-HD7 trial, half of the patients who received the anti-CD38 monoclonal antibody combined with RVd -- lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone -- achieved MRD negativity after induction therapy versus about a third of patients receiving RVd only, according to Hartmut Goldschmidt, MD, of the Heidelberg University Hospital and National Center of Tumor Diseases Heidelberg in Germany.

"The GMMG-HD7 trial is the first phase III trial powered to evaluate MRD negativity at the end of induction in transplant-eligible, newly diagnosed multiple myeloma patients," Goldschmidt said at a press briefing at the American Society of Hematology (ASH) annual meeting.

He added that the MRD-negativity rate achieved with the isatuximab-RVd combination "is the highest described to date in a randomized setting."

In March 2021, the isatuximab in combination with carfilzomib (Kyprolis) and dexamethasone for the treatment of adult patients with relapsed or refractory MM who have received one to three prior lines of therapy, based on results from the IKEMA trial.

The GMMG-HD7 trial (done from 2018-2020) included 662 patients from 67 sites in Germany who were randomized to receive three 42-day cycles of RVd alone, or in combination with isatuximab. The primary endpoint of the trial was MRD negativity assessed by next-generation flow after induction, with secondary endpoints including rates of complete response (CR) after induction, and safety. Of the 662 patients, 660 were included in the intent-to-treat analysis, and 658 were eligible for induction. Data cut-off for the current analysis was April 2021.

MRD-negativity rates after induction were 35.6% for RVd alone compared with 50.1% for the RVd/isatuximab combination (odds ratio 1.83, 95% CI 1.34-2.51, P<0.001).

On multivariate analyses (including treatment arm, performance status, renal impairment, age, and sex), treatment with isatuximab-RVd, compared with RVd alone, remained the only significant predictor for increased MRD negativity after induction (OR 1.82, 95% CI 1.33-2.49, P<0.001).

There was no difference in CR rates after induction between the RVd and isatuximab-RVd arms (21.6% vs. 24.2%, P=0.46). However, the investigators observed that the rate of very good partial response or better was significantly higher in the isatuximab-RVd arm (60.5% vs 77.3%, P<0.001). The rates of progressive disease were 4.0% in the RVd arm and 1.5% in the isatuximab-RVd cohort.

As for adverse events, "the addition of isatuximab had no impact on the safety profile or dose intensity of the RVd backbone," Goldschmidt reported.

He reported that at least one grade ≥3 adverse event (AE) on induction occurred in 61.3% of patients in the RVd cohort, and 63.6% in the RVd-isatuximab group. Rates of serious AEs on induction were similar between RVd and isatuximab-RVd (36.3% vs. 34.8%, P=0.75), while eight and four patients died during induction in the RVd and isatuximab-RVd groups, respectively.

As expected, rates of leukocytopenia and neutropenia were higher when isatuximab was added to RVd (26.4% vs 9.1% for RVd alone), "but this did not translate into increased rates of infection during induction treatment," Goldschmidt said.

The investigators observed that fewer patients discontinued treatment with isatuximab-RVd than with RVd alone, while the addition of the anti-CD38 monoclonal antibody had no impact on RVd-dose intensity.

When asked about the clinical relevance of MRD as an endpoint, Goldschmidt noted that advances in technology for evaluating MRD in myeloma have improved significantly over the last decade. He also pointed out there are ongoing discussions between the International Myeloma Working Group and the FDA about the in bone marrow in myeloma patients as an endpoint in clinical trials.

"I think the trial is a tremendous design for someone [like me] who treats more non-Hodgkin lymphoma," said press briefing moderator Laurie S. Sehn, MD, MPH, of the University of British Columbia in Vancouver. "We're desperately looking for surrogate markers that allow us to speed up the answers to clinical trials, and I think using MRD in myelomas is quickly becoming a very important surrogate marker."

"As we know, these patients with myeloma get these sequences of therapy, and its hard to pick out what component of the package is making an impact at each part of the treatment," she said, adding that "Being able to isolate out the importance of the induction regimen using MRD as an early surrogate is a very important design, and serves to demonstrate the utility isatuximab is adding to that regimen."

Goldschmidt noted that other studies presented at the ASH meeting will contain data on the importance of sustained MRD negativity, and observed that the GMMG-HD7 trial will evaluate whether MRD negativity is sustained with maintenance therapy. "We expect it will be a very good marker for the prognosis of myeloma patients," he stated.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

Goldschmidt disclosed relationships with Takeda, Sanofi, Incyte, Celgene, BMS, Janssen, MSD, Dietmar Hopp Foundation, Novartis, Amgen.

Primary Source

American Society of Hematology

Goldschmidt H, et al "Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone as Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial" ASH 2021; Abstract 463.